Recent Advances in classification

of Renal tumors

Speaker: Dr S.Gangaraju(2nd yr Pg)

Moderators: Dr Sujatha (Professor)
Dr Annapurna Sirisha
(Assoc. Prof)
DrShiva Chaitanya(Asst Prof)
• During the past several decades, considerable
advances have been made in our understanding of
the molecular pathogenesis of genitourinary tumors.

• This has led to greater understanding of the

molecular pathogenesis of renal cancer

• RCC classification may also carry significant clinical

implications for patients, including prognostic risk
stratification, selection of targeted therapeutics, and
identification for subsequent genetic testing (with
associated familial ramifications).
 Multilocular cystic renal neoplasm of
low malignant potential
• A tumour composed entirely of numerous cysts, the
septa of which contain small groups of clear cells
indistinguishable from grade Ι clear cell carcinoma.

• Macroscopy
• Multilocular cystic renal cell carcinoma consists of a
well-circumscribed mass of small and large cysts
filled with serous or haemorrhagic fluid and
separated from the kidney by a fibrous capsule.
• Histopathology
• The cysts are usually lined by a single layer of epithelial
cells or lack an epithelial lining. The lining cells may be
flat or plump and their cytoplasm ranges from clear to
pale.
• The nuclei almost always are small, spherical, and
have dense chromatin.
• The septa consist of fibrous tissue, often densely
collagenous. Within some of the septa there is a
population of epithelial cells with clear cytoplasm.
• The clear cells form small collections but do not form
expansile nodules.
• These epithelial cells often closely resemble
histiocytes, or lymphocytes surrounded by retraction
artefacts.
• Prior to the 2016 WHO classification, multilocular
cystic renal neoplasm of low malignant potential was
known as multilocular cystic RCC

• The name was changed to reflect the fact that, when

correctly diagnosed and classified using strict
morphologic criteria , there have been no reports of
recurrence or metastasis with long-term clinical
follow-up.
• There are no reliable immunophenotypic differences
between a multilocular cystic neoplasm of low
malignant potential and a low-grade, predominantly
cystic CCRCC

• Therefore, this differential diagnosis is resolved purely

on morphologic grounds, with a key discriminating
feature being the lack of expansile nests of tumor cells
within fibrous septae of multilocular cystic neoplasm of
low malignant potential
• The entity of papillary RCC has traditionally been
subdivided into type 1 and type 2 papillary RCCs.

• It has been accepted that a subset of tumours have

mixed histology.

• Recent molecular studies suggest that type 2 papillary

RCCs may constitute not a single well-defined entity
but rather individual subgroups with different
molecular backgrounds
• As previously mentioned, from a molecular
standpoint, type 2 PRCC represents a heterogeneous
group of molecularly distinct tumors and is currently
considered to be a diagnosis of exclusion

• Other RCC entities with papillary architecture (ie,

hereditary leiomyomatosis and RCC [HLRCC]–
associated RCC, collecting duct carcinoma [CDC],
among others) should be ruled out before rendering a
diagnosis of type 2 PRCC.
• In general, type 1 PRCC has a more favorable prognosis
than CCRCC

• A subset of patients, however, has high-grade and/or

locally advanced tumors, and a subset of tumors may
metastasize.

• Papillary adenomas are unencapsulated renal tumors

that are morphologically and immunophenotypically
identical to PRCC.
• In the past, a cutoff of 0.5 cm was used to distinguish
between papillary adenoma and PRCC

• Recent data with long-term follow-up, however,

indicate that tumors up to 1.5 cm with low-grade
nuclei (International Society of Urological Pathology
nuclear grades 1 or 2) have completely indolent
behavior.

• Therefore, the 2016 WHO classification has increased

the cutoff for PRCC to greater than 1.5 cm
Clear cell papillary renal cell carcinoma
• Clear cell papillary RCC is a newly recognized RCC
entity in the 2016 WHO classification.

• Although originally described in patients with end-

stage renal disease, CCPRCC is now recognized to
occur more commonly as a sporadic tumor in patients
without significant intrinsic kidney disease
• CCP-RCC is generally well defined and well
encapsulated. Cystic change or cystic formation is very
frequent.
• The tumors are usually small. The tumor is usually
solitary and unilateral, but multifocality and bilaterality
have been reported.
• The cut surface of the tumor shows tan-white, pink-
tan, yellow or red-brown color.
• Necrosis is absent, but focal hemorrhage may be
present
• Histopathology
• Composed mainly of cells with clear cytoplasm
arranged in papillary patterns
• Cysts of different sizes often containing
serosanguineous fluid or colloid-like secretion
• Branching tubules and acini and anastomosing clear
cell ribbons with low-grade nuclei
• Nuclei are oriented away from the basement
membrane and toward the apical surface of tubules
• Similar to multilocular cystic renal neoplasm of low
malignant potential, CCPRCC has a very good
prognosis, with essentially none to very rare reports of
recurrence or metastasis with long-term clinical follow-
up.

• Interestingly, in contrast to multilocular cystic renal

neoplasm of low malignant potential, CCPRCC does not
share common molecular alterations with CCRCC,
suggesting that it is truly a distinct molecular entity
from these tumor subtypes.
• Fortunately, the immunophenotype of CCPRCC is
distinctly different from CCRCC.
• Typically, CCPRCC is strongly and diffusely positive for
CK7.
• Usually, CA-IX is also strongly and diffusely positive but
shows a unique basolateral (“cuplike”) membranous
staining pattern, with a relative lack of staining at the
apical membrane in contrast to CA-IX expression in
CCRCC, which is strong and diffuse in a complete
membranous pattern.
• CCPRCC-like tumors can rarely occur in patients with
VHL
 MiT Family Translocation RCC (MiT
Family TRCC)
• Xp11.2 TRCC was established as an RCC subtype in
the 2004 WHO classification.
• In the 2016 WHO classification, Microphthalmia
associated transcription family TRCC, composed of
Xp11.2 TRCC and t(6;11) RCC, was newly defined as
an RCC subtype.
• Both Xp11.2 translocation and t(6;11) RCC are
characterized by the rearrangement of the MiT
transcription factors, TFE3 and TFEB
• Translocation RCC is associated with recurrent gene
fusions involving transcription factor binding to IGHM
enhancer 3 (TFE3; several different translocation
involving chromosome Xp11.2) or transcription factor
EB (TFEB; rearrangement between chromosome 6p21
and chromosome 11q12), which are both members of
the MiT family of transcription factors.

• These tumors were formerly classified as Xp11.2

translocation carcinoma; however, the name has been
changed in the 2016 WHO classification to reflect the
possibility of non-TFE3 fusion partners in the MiT
family (ie, TFEB).
• Gross Pathology
• Tumor generally forms a well circumscribed,
homogeneous, tan-yellow-brown mass

• Histopathology
• Tumors feature a solid, nested pattern of growth, and
demonstrated a biphasic population of neoplastic
cells:
• Polygonal epithelioid cells, with well-defined cell
borders, and abundant cytoplasm, either eosinophilic
and granular or clear
• A subpopulation (5% to 30%) of smaller cells with dark
nuclei clustering around hyaline material (basement
membrane), sometimes with globular configuration
• Tubular structures may be seen together with
micropapillary structures
• Neoplastic cells show clear cytoplasm with some
elements characterized by granular and eosinophilic
cytoplasm
• Mitoses are rare and necrosis is usually absent
• TFEB (nuclear staining): confirmatory
• Cathepsin K, kidney-specific cadherin: positive
• TFE3: negative
• HMB45, Melan A, vimentin: always focally positive
• Epithelial markers (AE1/3, cytokeratin 7,
cytokeratin20, EMA): negative
• From a genetic perspective, perhaps the most
important entity in the differential diagnosis of CCRCC
is MiT family translocation RCC (t-RCC) because these
tumors have distinct molecular alterations from CCRCC
and, therefore, may or may not respond to
conventional vascular endothelial growth factor
(VEGF)-based targeted therapies for CCRCC.
 Hereditary Leiomyomatosis and RCC-
Associated RCC (HLRCC-Associated RCC)

• Hereditary leiomyomatosis and RCC–associated RCC

is a newly recognized RCC entity in the 2016 WHO
classification.
• It is a relatively uncommon RCC subtype that has
morphologic and immunophenotypic overlap with
type 2 PRCC.
• Hereditary leiomyomatosis and RCC is associated with
germline mutations in the Krebs cycle gene fumarate
hydratase (FH) at chromosome 1q42.3-q43 , which
predisposes patients to the development of multiple
characteristic tumors, including cutaneous and uterine
leiomyomata and RCCs.

• Gross Pathology
• Typically unilateral and solitary tumors
• Frequently present at high stage with perinephric or
venous invasion
• Histopathology
• Architectural patterns include papillary, tubulopapillary,
tubular, and solid
• Resembles type II papillary RCC due to tall neoplastic
cells containing abundant eosinophilic cytoplasm lining
the papillae
• Cysts, focal clear cell areas, and cribriforming may also
be present
• Characteristic large nucleus with a very prominent
inclusion-like orangeophilic or eosinophilic nucleolus,
surrounded by a clear halo
• HLRCC-associated RCCs are typically negative for CK7,
CK20, and high–molecular-weight cytokeratin.
• Recently, immunohistochemistry for FH and S-(2-
succino)cysteine have been shown to be useful for
detecting HLRCC-associated RCCs.
• In these tumors, loss of heterozygosity at the FH locus
results in loss of cytoplasmic FH protein expression in
most cases
• In addition, loss of the FH protein function leads to
accumulation of aberrantly succinated proteins, which
can be detected as increased cytoplasmic/nuclear S-
(2-succinyl)cysteine expression.
• Together, these 2 immunostains have a high
sensitivity and specificity for detecting HLRCC-
associated RCCs.
• In general, HLRCC-associated RCC has an aggressive
clinical course, with frequent metastasis and
subsequent death.
• As such, the identification of patients with HLRCC-
associated RCC is important because these patients
(and their families) should undergo genetic
evaluation and counseling.
 Acquired Cystic Disease-Associated
RCC (ACD-Associated RCC)
• Acquired cystic disease (ACD)–associated RCC is a
newly recognized RCC entity in the 2016 WHO
classification.
• It is the most-common RCC subtype in patients with
end-stage renal disease and ACD (usually in the
setting of long-term hemodialysis or peritoneal
dialysis).
• Gross Pathology
• Multiple and bilateral tumors have been reported
• Mostly well demarcated
• Predominantly solid with varying extent of cystic
change
• Histopathology
• Tumors show variegated architecture forming diffuse
sheets, macro- and microcysts, tubulopapillary
arrangements, and nests
• Characteristic inter- or intracellular microlumen
formation and intratumoral deposition of oxalate
crystals
• Large tumor cells with eosinophilic cytoplasm and
mildly irregular nuclei
• Proliferation and multilayering are occasionally
present, creating papillary projections and small nests
• These tumors often show variable chromosomal
gains, including chromosomes 7 and 17 (which are
more classically associated with PRCC).
• ACD-associated RCC can show overlapping
morphologic and immunophenotypic features with
PRCC
• Although these tumors frequently express AMACR
and CD10, ACD-associated RCC is usually negative for
CK7 expression.
• In general, ACD-associated RCC is an indolent tumor;
however, a subset of patients with ACD-associated
RCC may develop metastatic disease.
 Succinate Dehydrogenase-Deficient
RCC (SDH-Deficient RCC)
• Succinate dehydrogenase (SDH)–deficient RCC is a
newly recognized RCC entity in the 2016 WHO
classification.

• It occurs predominantly in patients with germline

mutations in one of the SDH genes: SDHA, SDHB
(most commonly), SDHC, and SDHD. These tumors
usually arise in younger patients but have a large age
range
• Patients may also have paragangliomas and
gastrointestinal stromal tumors.

• Gross Pathology
• Typically unilateral and solitary tumor
• Well circumscribed or lobulated tumors frequently
showing cystic change
• Histopathology
• SDHB mutation associated tumors show oncocytic
features
• Composed of cuboidal cells with bubbly eosinophilic
cytoplasm, indistinct cell borders, centrally placed
nucleoli, and inconspicuous nucleoli
• Distinctive cytoplasmic inclusions, either vacuolated or
containing eosinophilic fluid-like material
• Cells are arranged in solid nests or in tubules
surrounding central spaces
• Succinate dehydrogenase–deficient RCC is typically
negative for CD117 and CK7 expression.

• Immunohistochemistry with SDHA and SDHB is useful

(and, perhaps, even required) for the diagnosis of
SDH-deficient RCC; loss of cytoplasmic SDHA staining
indicates a mutation in SDHA, whereas loss of
cytoplasmic SDHB staining signifies a mutation in
either SDHB, SHDC, or SDHD .
• Most SDH-deficient RCCs are low-grade neoplasms
with an indolent clinical course,

• However, a distinct subset of patients with

dedifferentiation or presence of coagulative necrosis
may develop metastatic disease and/or late
recurrences.

• Genetic evaluation and counseling should be

recommended for all patients with SDH-deficient RCC
 Tubulocystic renal cell carcinoma
• Tubulocystic RCC is a newly recognized RCC entity in
the 2016 WHO classification.

• It is a rare, often incidentally discovered, RCC

subtype, which typically occurs in older patients and
shows a slight male predominance
• Gross Pathology
• Microcystic mass with a bubble-wrap appearance
• White spongy mass made of thin-walled translucent
cysts filled with clear watery fluid
• Well demarcated from normal parenchyma, but not
encapsulated
• No solid components
• Histopathology
• Tumor with a tubulocystic architecture composed of
cysts and small tubules, separated by delicate septa or
by fibrotic stroma
• Tubules and cysts are lined by flat to columnar or
hobnail eosinophilic cells
• Nuclei are regular, round to oval, with prominent
nucleoli
• Similar to PRCC, tubulocystic RCC typically expresses
CK7, AMACR, and CD10 and often demonstrates gains
of chromosomes 7 and 17.

• Overall, tubulocystic RCC is an indolent tumor, with

only rare reports of metastasis

• Tubulocystic-like morphology may be seen in patients

with HLRCC-associated RCC, and cases with
dedifferentiated tubulocystic morphology may actually
represent a subset of HLRCC-associated RCC.
• Mixed epithelial and stromal tumours (MEST)
• Encompass a spectrum of tumours including
predominantly cystic tumours (adult cystic nephromas)
and tumours that are more solid.
• Adult cystic nephroma was previously classified, along
with paediatric cystic nephroma, as a separate entity
from MEST.
• On the basis of similar age and sex distributions and a
similar histochemical profile, adult cystic nephroma is
now classified within this spectrum of MEST,
• The WHO renal tumour subcommittee recommended
using the term mixed epithelial and stromal tumour
family for both entities.
• In contrast to adult cystic nephroma, paediatric cystic
nephroma is a distinct entity with specific DICER1
mutations
• Most carcinoids of the kidney have a poor prognosis,
with frequent occurrence of metastasis after
nephrectomy.

• The renal tumour subcommittee recommended renal

carcinoids should be newly designated as well-
differentiated neuroendocrine tumours of the kidney
and simultaneously placed within the group of
endocrine tumours encompassing small cell
neuroendocrine carcinomas, large cell neuroendocrine
carcinomas, and paragangliomas (extrarenal
pheochromocytoma).
• Grading of renal tumours
• Many grading systems have been proposed for renal
cell neoplasia.
• The Fuhrman system was the most frequently used
grading system in RCC but should not be applied for
chromophobe RCC .
• Furthermore, the Fuhrman system has not been
validated for most of the new subtypes of
renalcarcinoma.
• For these reasons, the four-tiered WHO/ISUP grading
system is recommended by the WHO
• Very few thyroid-like follicular RCCs have been
described
• Fewer than 10 RCCs associated with ALK gene
rearrangements have been reported in the literature
some are medullary based tumours.
• Recently, reports of RCC associated with prominent
angioleiomyomatous stroma have been published.
• It is unclear if the renal angiomyoadenomatous
tumour represents a variant of ccRCC or clear cell
papillary RCC
• A recent report identified TCEB1 gene mutations in
tumours with this morphology
•

• THANK YOU
References
• WHO Kidney and MGT 4th edition
• 2016-WHO-ClassificationTumours GTract- Part A-Kidney Penis
Testicle
• Renal Cell Tumors: Understanding Their Molecular Pathological
Epidemiology and the 2016 WHO Classification
• Morphologic, Molecular, and Taxonomic Evolution of Renal Cell
Carcinoma: A Conceptual Perspective With Emphasis on Updates to
the 2016 World Health Organization Classification